An ever-increasing demand exists for materials and methods that provide continuous, noninvasive or minimally invasive glucose monitoring because of the increase in the number of people diagnosed with diabetes mellitus, more commonly referred to as type 1, insulin dependent diabetes. Clark, Jr., Diabetes Care, 21:Supp. 3, C1 (1998); Davidson, Diabetes Care, 21:2152 (1999). The need for minimally invasive glucose monitoring has also increased due to the recognition that the long-term health of patients with diabetes mellitus is dramatically improved with careful glucose monitoring and control. Picup et al., BMJ, 319:1289 (1999). However, many methodologies for glucose monitoring are invasive and often show poor patient compliance, which leads to negative health consequences for the patient.
The need for minimally invasive, easy-to-use glucose sensors and methods of detecting glucose concentration has motivated the investigation of numerous approaches. For example, early work in near-infrared absorption spectroscopy, which took advantage of tissue transparency in the 600 to 1300 nm spectral range, showed initial promise as a truly non-invasive glucose sensor. Heinemann et al., Diabetologia, 41:848 (1998). In this technique, near-infrared radiation is allowed to penetrate biological tissues within the therapeutic window of 600 to 1300 nm, and the spectrum of the tissue is then acquired through either a transmission or a reflectance measurement. Arnold et al., Anal. Chem., 70:1773 (1998). The acquired spectrum contains a mixture of overlapping spectral bands for the various components of the tissue, such as water, fat, protein, and glucose, and the spectrum is used to determine the level of glucose in the tissue. However, the accuracy of this technique is negatively affected by factors such as blood flow and temperature, which are difficult to control.
Various optical methods have also been investigated for noninvasive glucose monitoring. For example, luminescent glucose sensors have been developed based on the intrinsic green fluorescence of the glucose oxidase enzyme (referred to herein as “GOD”), the enzyme involved in the conversion of glucose to gluconic acid. Trettnak et al., Analytica Chimica Acta, 221:195 (1989). The flavin moiety, which is present at the active site of the GOD, becomes reduced when glucose is converted to gluconic acid. Because the flavin moiety and its reduced form exhibit different fluorescence spectra, the change in the fluorescence spectrum of the GOD may be monitored to determine the glucose concentration in a solution or fluid.
Other researchers have attached fluorescent probes to the GOD molecule for fluorescence-based glucose sensing, since the binding of glucose to the GOD molecule changes the fluorescence probe. James et al., Angewandte Chemie Int'l Edition in English, 33:2207 (1994). In another approach, fluorescent probes are attached to glucose binding proteins (also called maltose binding proteins), where the glucose binding proteins undergo dramatic conformational changes which alter the fluorescence of the probe. Marvin et al., Proc. Natl. Acad. Sci., USA, 94:4366 (1997); Marvin et al., J. Am. Chem. Soc., 120:7 (1998). Additionally, other techniques such as photoacoustic spectroscopy (MacKenzie et al., Clinical Chemistry, 45:1487 (1999)), near-infrared absorption spectroscopy (Gabriely, et al., Diabetes Care, 22:2026 (2000)), and near-infrared fluorescence spectroscopy (Rolinski et al., J. Photochem. Photobiol. B: Biology, 54:26 (2000)) have also been investigated for determining the level of glucose in tissues.
Recently, various minimally invasive approaches to glucose monitoring have attempted to determine glucose levels in extracted interstitial fluid. These approaches utilize microdialysis (Boutelle et al., Anal. Chem., 64:1790 (1992)) or electric fields (Tamada et al., Diabetes, 47:Supp. 1, 62A (1998)) to obtain the interstitial fluids through the skin, and such techniques use primarily electrochemical methods to determine the glucose concentration. The last approach has been commercialized as a watch-type device to electrochemically determine the glucose level in fluid that is extracted through the skin. Picup et al., BMJ 319:1289 (1999). However, the perspiration on a patient's skin may interfere with the accuracy of such a watch-type device.
More invasive approaches of glucose monitoring involve the implantation of electrochemical and fluorescent sensors in tissue. For example, one approach provides for the monitoring of the intensity of the fluorescence of the glucose sensors through the skin by using small external spectrometers. Ballerstadt et al., Anal. Chem., 72:4185 (2000). Other approaches provide for the implantation of electrochemical glucose sensors within the body, and some of these approaches utilize external circuits to determine the electrochemical signals given off by the glucose sensors, while others completely implant the sensors and utilize various remote readouts to monitor glucose levels. Wilson et al., Clin. Chem., 1613 (1992). All of these approaches to glucose monitoring face the challenges of sensor stability, tissue rejection, ease of use, and cost.
A variety of electrochemical glucose sensors are known in the art. One such electrochemical glucose sensor involves an amperometric enzyme electrode, which uses immobilized glucose oxidase (GOD). Generally, the conversion of glucose to gluconic acid can be described by the following reaction scheme:GOD-FAD+β-D-glucose→GOD-FAD·H2+D-glucono-δ-lactoneGOD-FAD·H2+O2→GOD-FAD+H2O2  (1)wherein “FAD” represents the flavine-adenine dinucleotide prosthetic group that is attached to the GOD enzyme, while FAD·H2 represents the reduced form of FAD. Referring to the above reaction scheme, GOD amperometric sensors are able to monitor the concentration of glucose by monitoring the change in the flow of current caused by the electrochemical reduction of hydrogen peroxide as shown in the reaction designated “(1)” in the above scheme.
Another electrochemical glucose sensor that utilizes GOD involves the use of pH-responsive hydrogels. Dorski et al., Polym. Prepr., 37:475 (1996); Podual et al., Biomaterials, 21:1439 (2000); Jung et al., Macromolecules, 33:3332 (2000). The GOD-induced catalysis of glucose to gluconic acid results in a decrease in the pH of the solution. This pH decrease actuates the swelling or shrinking of the hydrogel materials. These hydrogel volume changes alter the diffusion constant of electrochemically active species in the solution. The resultant changes in the electrochemistry (for example, changes in conductivity and current flow) may be used to monitor the glucose concentration. Such an approach may also be useful for developing in vivo insulin supplying devices. Schwarte et al., Polym. Prepr., 38:596 (1997); Bell et al., Biomaterials, 17:2023 (1996). This type of electrochemical approach to detecting glucose in a solution require the use of electrical wires and instrumentation.
Other electrochemical approaches for monitoring glucose levels in fluids have utilized polymer hydrogels that have been functionalized with phenylboronic acids, which bind glucose and other diols. Kitano et al., Makromol. Chem., Rapid Commun., 12, 227–233 (1991). The binding of glucose results in the swelling or shrinking of a hydrogel, where the hydrogel is coated on the surface of an electrode. The changing volume of the hydrogel is monitored through its effects on the diffusion constant of electrochemically active species with respect to the electrode. Even though the detection scheme for measuring glucose levels disclosed by Kitano et al. employs a hydrogel that swells and shrinks, such an electrochemical sensing method requires the use of electrical wires and instrumentation in order to detect glucose levels. Thus, a hydrogel glucose sensor according to Kitano et al. could not be used in a contact lens type format nor as an optical insert, as it would be impossible to connect electrical wires and/or instrumentation to the sensor while the sensor is in a patient's eye.
As mentioned above, some glucose sensors known in the art have employed polymer hydrogels. For example, glucose sensing materials have been disclosed which comprise a polyacrylamide hydrogel wherein a crystalline colloidal array is embedded. The polymerized crystalline colloidal array chemical sensing materials (which have been referred to as “PCCA”s) have been described in, for example, U.S. Pat. Nos. 6,187,599, 5,854,078, and 5,898,004, all of which are hereby incorporated by reference in their entireties herein. Such PCCA materials have been described with respect to their ability to detect metal cations, pH, ionic strength, and the concentration or level of glucose.
In previous disclosures where PCCA chemical sensing materials have been used in conjunction with measuring levels of glucose, the sensing materials have relied upon GOD, the enzyme described earlier. Specifically, the conversion of glucose to gluconic acid, which is catalyzed by the GOD enzyme, results in the reduction of FAD, whereby the FAD becomes negatively charged and causes the hydrogel (in which the PCCA is embedded) to swell. This swelling of the hydrogel results in a red-shift of the Bragg diffraction, which enables a user to determine the concentration of glucose.
A need exists for the development of accurate, reliable, continuous, and noninvasive or minimally invasive glucose sensors that may improve the lives of patients having diabetes and may decrease such patients' risk of developing hypoglycemia and hyperglycemia.